US2894872A - Cycloheximide beta-keto-carboxylic acid esters - Google Patents

Cycloheximide beta-keto-carboxylic acid esters Download PDF

Info

Publication number
US2894872A
US2894872A US653292A US65329257A US2894872A US 2894872 A US2894872 A US 2894872A US 653292 A US653292 A US 653292A US 65329257 A US65329257 A US 65329257A US 2894872 A US2894872 A US 2894872A
Authority
US
United States
Prior art keywords
cycloheximide
beta
keto
ester
degrees centigrade
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Expired - Lifetime
Application number
US653292A
Other languages
English (en)
Inventor
Maxton F Murray
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Pharmacia and Upjohn Co
Original Assignee
Upjohn Co
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority to NL108583D priority Critical patent/NL108583C/xx
Application filed by Upjohn Co filed Critical Upjohn Co
Priority to US653292A priority patent/US2894872A/en
Priority to DE19581420104 priority patent/DE1420104A1/de
Priority to GB10443/58A priority patent/GB857167A/en
Application granted granted Critical
Publication of US2894872A publication Critical patent/US2894872A/en
Anticipated expiration legal-status Critical
Expired - Lifetime legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/80—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
    • C07D211/84—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen directly attached to ring carbon atoms
    • C07D211/86—Oxygen atoms
    • C07D211/88—Oxygen atoms attached in positions 2 and 6, e.g. glutarimide
    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
    • A01N37/00—Biocides, pest repellants or attractants, or plant growth regulators containing organic compounds containing a carbon atom having three bonds to hetero atoms with at the most two bonds to halogen, e.g. carboxylic acids
    • A01N37/42—Biocides, pest repellants or attractants, or plant growth regulators containing organic compounds containing a carbon atom having three bonds to hetero atoms with at the most two bonds to halogen, e.g. carboxylic acids containing within the same carbon skeleton a carboxylic group or a thio analogue, or a derivative thereof, and a carbon atom having only two bonds to hetero atoms with at the most one bond to halogen, e.g. keto-carboxylic acids

Definitions

  • This invention relates to novel compounds, compositions, and processes. More particularly, it is directed to esters of cycloheximide and lower-beta-keto hydrocarboncarboxylic acids, to a process for preparing said esters, and to their use for preventing and arresting the infestations of fungi, insects, and other pestiferous organisms which are economically harmful to man.
  • R is an acyl group derived from a lower-betaketo hydrocarboncarboxylic acid containing not more than ten carbon atoms.
  • cycloheximide 3-[2-(3,5-dimethyl-2- oxocyclohexyl)Z-hydroxyethyllglutarimide
  • the active compound can be isolated from fermentative beers resulting from a culture of Streptomyces grlseus on a suitable nutrient medium according to methods described in United States Patents 2,574,519 and 2,612,502.
  • lower-beta-keto hydrocarboncarboxylic acid esters of cycloheximide are much less phytotoxic than cycloheximide itself, yet they possess equivalent activity against many of the pest organisms controlled by cycloheximide.
  • these lower-beta-keto esters are systemic plant fungicides. Consequently, they can be applied to growing plants and subsequent growth is protected from fungal disease. This superiority is of great significance when plants are growing rapidly, because control of infection can be maintained in spite of longer intervals between spray applications.
  • Systemic activity is otherwise advantageous, because the compounds are adaptable to methods of application that are less exacting than thorough coverage by sprays, and which require less expensive equipment.
  • the lower-beta-keto hydrocarboncarboxylic acid esters of cycloheximide can be formulated with aqueous or non-aqueous carriers for application of foliage, seeds, or other parts of plants.
  • Compositions suitable for root or bole infusion can also be made. Since the compounds of the in ention are very slightly soluble in water, it is desirable to first dissolve the compound in a water-miscible solvent such as dimethylformamide, dimethylacetamide, dimethyl sulfoxide, acetonitrile, cyclohexanone, or a similar solvent.
  • Dimethylformamide, dimethylacetamide and dimethyl sulfoxide are preferred, because the lower-beta-keto esters of cycloheximide are highly soluble therein.
  • Such concentrated solutions can then be admixed with a suitable volume of an aqueous medium to give a mixture of any desired concentration.
  • mixtures containing very low concentrations of the active ingredient are effective.
  • the concentration of loWer-beta-keto ester can range from about 0.5 to about parts per million, or even higher, such as up to the practical limits of maintaining a homogeneous dispersion of the components.
  • a concentrate comprising one percent (by weight) of ester dissolved in a Water-miscible solvent of the kind noted above can be admixed with an aqueous medium in the proportions of one teaspoonful (5 cc.) of concentrate with one gallon of medium to give a mixture containing thirteen to fourteen parts of active ingredient per million parts of water.
  • One pint of a one percent concentrate mixed with 100 gallons of water provides about twelve parts per million of active ingredient.
  • more concentrated solutions of an active ingredient in a watermiscible solvent can be incorporated with an appropriate quantity of aqueous. medium to give a preparation of desired concentration.
  • the loWer-beta-keto esters of cycloheximide can be formulated and can be applied as foliar sprays, as.
  • compositions for root or bole infusion or as mixtures for treatment of seeds.
  • cyclohexanone as solvent in making up the concentration and to include in the final spray mixture a small amount (about 0.25 to 1.0 percent by volume) of a non-phytotoxic oil such as summer oil.
  • adjuvants such as wetting agents, spreading agents, dispersing agents, stickers and adhesives, and the like in accordance with usual agricultural practices.
  • Anionic, cationic, and non-ionic surfactants can be used.
  • Suitable surfactants include alkyl sulfates and sulfonates, alkylarylsulfonates, sulfosuccinate esters, polyoxyethylene sulfates, polyoxyethylene sorbitan monolaurate, alkylarylpolyether sulfates, alkylarylpolyether alcohols, alkyl quaternary ammonium salts, sulfated fatty acid esters, sulfated fatty acid amides, glycerol mannitan laurate, polyalkylether condensates of fatty acids, ligninsulfonates, and the like.
  • the active material can be compounded with a powder carrier.
  • a powder carrier such as talc, pyrophyllite, Georgia clay, bentonite, or mixtures thereof, with or without adjuvants such as those mentioned above to provide com,- positions which can be used for treating'seeds, or for the dusting of plants, or for preparing aqueous sprays for application to foliage.
  • a suitable formulation is obtained by milling and blending 434.5 pounds of Georgia clay, 4.5 pounds of Triton X-l (an alkylarylpolyether alcohol) as a wetting agent, nine pounds of Daxad 27 (polymerized sodium salt of, substituted benzoid longchain alkyl sulfonic acid) as a dispersant and about 5.5- pounds of a lower-beta-keto ester of cycloheximide.
  • the resulting mixture has the following percentage (by weight) composition.
  • This formulation when added to water at one pound per hundred gallons gives a spray mixture containing about thirteen to fourteen parts per million of active ingredient.
  • the compounds of the invention are particularly useful as plant disease fungicides and have been more particularly described above in connection therewith, they are likewise useful generally in controlling fungi which commonly infest and attack plant and animal matter either in its natural or fabricated state, e.g., rawhide, glue, gelatin, leather, cork, wood, cotton fabric, cordage, ink, casein products, etc. Moreover, the compounds of the invention have been demonstrated to possess insecticidal properties, as well as activity against other pest organisms.
  • the compounds of the invention can be prepared by a transesterification reaction involving equimolar amounts of cycloheximide and a lower-alkyl ester, such as the methyl or ethyl ester, of the desired lower-beta-keto hydrocarboncarboxylic acid.
  • a transesterification reaction involving equimolar amounts of cycloheximide and a lower-alkyl ester, such as the methyl or ethyl ester, of the desired lower-beta-keto hydrocarboncarboxylic acid.
  • an excess such as about a two-fold or threefold excess, of the keto ester, in which case the excess serves as a solvent or diluent for carrying out the reaction; other solvents or diluents such as benzene, toluene, xylene, and the like can be employed.
  • the reaction can be carried out at temperatures ranging from about fifty degrees centigrade to about 200 degrees centigrade, steam bath
  • the removal of alcohol formed by transesterification may be facilitated by bubbling a stream of inert gas such as nitrogen through the reaction mixture during the heating period, but this is not necessary.
  • inert gas such as nitrogen
  • the excess betaketo ester reactant is removed by distillation under a partial vacuum.
  • the viscous, oily residue is dissolved in a suitable inert solvent such as benzene and the lowerbeta-keto hydrocarboncarboxylic acid ester of cycloheximide is recovered by known methods such as solvent extraction, crystallization, chromatographic separation, etc.
  • beta-keto esters of the kind noted above are suitable as starting materials for the practice of the invention, and such esters can be prepared by methods known in the art [see Hauser and Hudson, Organic Reactions 1: pp. 266-302 (1942)].
  • Some examples of such betaketo esters are: ethyl acetoacetate, methyl acetoacetate, propyl acetoacetate, ethyl u propionylpropionate, ethyl ubutyrylbutyrate, ethyl a-isobutyrylisobutyrate, ethyl oc-Ilvaleryl-n-valerate, ethyl propionylacetate, ethyl n-butyrylacetate, ethyl n-valerylacetate, ethyl a-formylpropionate,
  • the product was then dissolved in 125 milliliters of methanol at room temperature and allowed to stand. Precipitation occurred in above five minutes and resulted in a semi-solid mass. Another 125- milliliters of meth anol were added and the mixture was filtered. This product was washed with methanol and dried at fifty degrees centigrade under partial vacuum. The resulting crude cycloheximide acetoacetate methyl alcoholate weighed 32.0 grams (35 percent) and gave a melting point of 67-70 degrees centigrade (upon solidification it remelted at -110 degrees centigrade). An analytical sample was obtained by dissolving one gram of the methyl alcoholate in forty milliliters of 1:1 methanol and isoproyl ether, and then concentrating the solution After cooling, the solids were.
  • R is a lower-beta-keto hydrocarboncarbonyl group containing not more than ten carbon atoms.
  • a method of protecting plants from damage caused by fungal disease which comprises applying to said plants, in fungicidal toxic amount, lower-beta-keto ester of cycloheximide in a dispersed state.
  • a method of protecting plants from damage caused by fungal disease which comprises applying to the foliage of said plants, in fungicidal toxic amount, an aqueous spray containing lower-beta-keto ester of cycloheximide.
  • a method of protecting plants from damage caused by fungal disease which comprises applying to the foliage of said plants, in fungicidal toxic amount, an aqueous spray containing cycloheximide acetoacetate.
  • composition for the control of plant disease fungi which comprises, as an essential active ingredient, lower-beta-keto ester of cycloheximide and a dispersi-ble carrier therefor.
  • composition of claim 8 wherein the dispersible carrier is a wettable inert powder.
  • composition for the control of plant disease fungi which comprises, as an essential active ingredient, lower-beta-keto ester of cycloheximide dissolved in a water-miscible solvent.
  • composition for the control of plant disease fungi which comprises, as an essential active ingredient, lower-beta-keto ester of cycloheximide dissolved in dimethylformamide.
  • a process for preparing lower-beta-keto hydrocarboncarboxylic acid esters of cycloheximide which comprises mixing and heating a lower-alkyl ester of lower-beta-keto hydrocarboncarboxylic acid with cycloheximide, and recovering the lower-beta-keto hydrocarboncarboxylic acid ester cyclohexemide thus formed.
  • ester reactant is dimethyl B-oxoglutarate.
  • a composition for the control of plant disease fungi which comprises as an essential active ingredient, cycloheximide acetoacetate in aqueous spray solution.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Agronomy & Crop Science (AREA)
  • Pest Control & Pesticides (AREA)
  • Plant Pathology (AREA)
  • Health & Medical Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Dentistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Wood Science & Technology (AREA)
  • Zoology (AREA)
  • Environmental Sciences (AREA)
  • Agricultural Chemicals And Associated Chemicals (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
US653292A 1957-04-17 1957-04-17 Cycloheximide beta-keto-carboxylic acid esters Expired - Lifetime US2894872A (en)

Priority Applications (4)

Application Number Priority Date Filing Date Title
NL108583D NL108583C (forum.php) 1957-04-17
US653292A US2894872A (en) 1957-04-17 1957-04-17 Cycloheximide beta-keto-carboxylic acid esters
DE19581420104 DE1420104A1 (de) 1957-04-17 1958-03-29 Cycloheximidderivate und Verfahren zu ihrer Herstellung
GB10443/58A GB857167A (en) 1957-04-17 1958-04-01 Esters of cycloheximide and pesticidal compositions containing same

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
US653292A US2894872A (en) 1957-04-17 1957-04-17 Cycloheximide beta-keto-carboxylic acid esters

Publications (1)

Publication Number Publication Date
US2894872A true US2894872A (en) 1959-07-14

Family

ID=24620253

Family Applications (1)

Application Number Title Priority Date Filing Date
US653292A Expired - Lifetime US2894872A (en) 1957-04-17 1957-04-17 Cycloheximide beta-keto-carboxylic acid esters

Country Status (4)

Country Link
US (1) US2894872A (forum.php)
DE (1) DE1420104A1 (forum.php)
GB (1) GB857167A (forum.php)
NL (1) NL108583C (forum.php)

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3014840A (en) * 1959-04-22 1961-12-26 Upjohn Co Improved formulation of cycloheximide compositions and process for the control of blister rust and like fungal infections in trees
US3086913A (en) * 1962-04-27 1963-04-23 James M Hamilton Systemic fungicides

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
None *

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3014840A (en) * 1959-04-22 1961-12-26 Upjohn Co Improved formulation of cycloheximide compositions and process for the control of blister rust and like fungal infections in trees
US3086913A (en) * 1962-04-27 1963-04-23 James M Hamilton Systemic fungicides

Also Published As

Publication number Publication date
NL108583C (forum.php)
GB857167A (en) 1960-12-29
DE1420104A1 (de) 1969-03-06

Similar Documents

Publication Publication Date Title
US3725428A (en) N-benzothiazol-2-yl-n{40 -propylureas
EP0808297B1 (de) Verwendung von schwerflüchtigen pyrazolderivaten mit hydrophilen gruppen als nitrifikationsinhibitoren
EP0483062B1 (de) Verfahren zur Herstellung von Nitroguanidinderivaten
US3122557A (en) New coumarin-and alpha-pyrone-3-carboxamides
US4033754A (en) Substituted cyclohexene esters
US2894872A (en) Cycloheximide beta-keto-carboxylic acid esters
US4002754A (en) Substituted piperazinyliminorifamycins
US4346225A (en) Herbicidal 2-methylamino thiadiazolines
US2963399A (en) Fungicidal polychlorobenzophenone oximes
US2885320A (en) Cycloheximide thiosemicarbazone
US2663665A (en) N-naphthyl maleamic esters
US4105764A (en) 4,5-Dihydro-5-oxopyrazolo[1,5-A]quinazoline-3-carboxamides
US3488362A (en) Lenthionine and a process for the preparation thereof
US3749747A (en) Substituted cinnanyl thiocyanates and their isomers
US3671535A (en) 4-imino-oxazolidin-2-ones and process of preparation
EP0081584B1 (en) Thiazolinotriazine derivatives
US2790749A (en) Nu-trichloromethylthio-4, 5-dimethyltetrahydrophthalimide and fungicidal composition containing same
US2857396A (en) Hydroxyphthalimidines
US2894871A (en) Alkyl hydrazones of cycloheximide
US2980580A (en) Cycloheximide acetate horticultural fungicidal composition and method of use
JP3090995B2 (ja) ３，４−トランス−４−エチル−３−（置換フェニル）−１−（３−イソプロピルフェニル）−２−ピロリジノン誘導体、
US2870144A (en) 3-furfurylidene-aminmo-1, 2, 4-triazole and process for producing same
US2975186A (en) Certain haloalkylolamino pyridines
DE19712411A1 (de) Verfahren zur Herstellung von 1,3-disubstituierten 2-Nitroguanidinen
US2982687A (en) Anhydrocycloheximide and its horticultural fungicidal use